Nilotinib, 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)-phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, having the following formula:
is a tyrosine kinase inhibitor used for the treatment of drug-resistant chronic myelogenous leukemia (CML), and in particular, for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive CML in adult patients whose disease has progressed, or who cannot tolerate other therapies that include imatinib. Nilotinib is administered as a hydrochloride salt in the form of capsules that are marketed in the USA and the EU under the name Tasigna®.
PCT publications WO 2007/015870 (“WO '870”) and WO 2007/015871 (“WO '871”) describe several Nilotinib salts, including crystalline and amorphous forms of nilotinib free base, Nilotinib hydrochloride and Nilotinib Sulfate. The crystalline forms exist in either solvate, anhydrous or hydrate forms. PCT publication no. WO 2007/015870 (WO '870) describes crystalline forms of nilotinib including Nilotinib HCl crystalline form A. PCT publication no. WO 2010/054056 (‘WO '056’) describes crystalline forms of nilotinib HCl including Nilotinib HCl crystalline forms T17, T18 and T19. PCT publication no. WO 2011/033307 describes Nilotinib dihydrochloride salt and a crystalline form thereof.
The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.
The present invention relates to salts of Nilotinib; 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide and their solid state forms. The salts are selected from: Nilotinib HCl, Nilotinib fumarate, Nilotinib 2-chloromandelate, Nilotinib succinate, Nilotinib adipate, Nilotinib L-tartrate, Nilotinib glutarate, Nilotinib p-toluenesulfonate, Nilotinib camphorsulfonate, Nilotinib glutamate, Nilotinib palmitate, Nilotinib quinate, Nilotinib citrate, Nilotinib maleate, Nilotinib acetate, Nilotinib L-malate, Nilotinib L-aspartate, Nilotinib formate, Nilotinib hydrobromide, Nilotinib oxalate and Nilotinib malonate. The nature of the solid form can be influenced by controlling the conditions under which the above 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide salts are obtained. Preferably, the present invention relates to solid state forms of Nilotinib hydrobromide and Nilotinib L-tartrate.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis—(TGA), or differential scanning calorimetry—(DSC)), X-ray powder diffraction (XRPD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new salts and new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional polymorphs of Nilotinib salts.